Genome-wide association study

Pathology

Transcriptome

Neuroscience

Genomics

Disease

Biology

Gene

Induced pluripotent stem cell

Genotype

Embryonic stem cell

Gene expression

Genome

Genetic association

Single-nucleotide polymorphism

Motor neuron

Amyotrophic lateral sclerosis

Spinal cord

Candidate gene

Computational biology

Genetics

Medicine

Neuron

Amyotrophic lateral sclerosis (ALS) is a complex disease that leads to motor neuron death. Despite heritability estimates of 52%, genome-wide association studies (GWASs) have discovered relatively few loci. We developed a machine learning approach called RefMap, which integrates functional genomics with GWAS summary statistics for gene discovery. With transcriptomic and epigenetic profiling of motor neurons derived from induced pluripotent stem cells (iPSCs), RefMap identified 690 ALS-associated genes that represent a 5-fold increase in recovered heritability. Extensive conservation, transcriptome, network, and rare variant analyses demonstrated the functional significance of candidate genes in healthy and diseased motor neurons and brain tissues. Genetic convergence between common and rare variation highlighted KANK1 as a new ALS gene. Reproducing KANK1 patient mutations in human neurons led to neurotoxicity and demonstrated that TDP-43 mislocalization, a hallmark pathology of ALS, is downstream of axonal dysfunction. RefMap can be readily applied to other complex diseases.

Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis